Polymer-lipid hybrid microcarriers for oral codelivery of paclitaxel and tributyrin: development, optimization, and cytotoxicity in cells and spheroids of colorectal cancer

Author(s)

Fukumori, Claudio ; Kawassaki, Rodrigo Ken ; Dare, Regina G. ; Lopes, Luciana B.

• Document type: Journal article
• Source: International Journal of Pharmaceutics; v. 676, p. 15-pg., 2025-04-16.

Abstract

Colorectal cancer (CRC) is the third most frequent cancer worldwide. Despite advances in treatment, conventional chemotherapy suffers from severe side effects and limited drug selectivity, highlighting the importance of alternative therapies. In this study, a polymer-lipid hybrid microcarrier was developed for oral co-administration of paclitaxel (PTX) and tributyrin (TB) as a novel approach for CRC therapy. The microcarrier was designed with a pH-sensitive polymeric shell that encapsulates drug-loaded nanostructured lipid carriers (NLC); shell dissolution at intestinal pH enables localized release of the NLC. The methodological approach employed an emulsion of vegetable oil and NLC as a template for polymer deposition. Multiple parameters were optimized, including polymers ratios, NLC dilution, acid concentration, and sonication time. Spherical hybrid particles with smooth surface and mean size of 1000 nm were obtained; PTX encapsulation efficiency was 99.9 +/- 0.2 %, with a production yield of 97.2 +/- 0.08 %. Drug release followed the Korsmeyer-Peppas kinetic model. Cytotoxic evaluation in human colorectal adenocarcinoma HCT-116 monolayers showed that PTX encapsulation increased cytotoxicity, lowering IC50 to 83.7 nM compared to 199.5 nM for free PTX. The addition of TB further improved cytotoxicity, reducing the IC50 to 60.8 nM. A similar potentiation cytotoxicity was observed in spheroids. The microcarrier induced reductions in colony formation, alterations in cell cytoskeleton, and led to a significant reduction in P-glycoprotein expression compared to its free form, suggesting its potential to help to overcome drug resistance. These results point to the promising applicability of the hybrid microcarrier as an innovative delivery system for oral administration of cytotoxic agents. (AU)

• FAPESP's process: 22/12876-7 - Study of pectin-chitosan systems enriched with nanostructured lipid carriers for the delivery of nisin, simvastatin and adenosine aiming the treatment of skin ulcers
• Grantee: Regina Gomes Daré
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 19/03241-5 - Preparation and evaluation of oral nanocarriers of 5-fluorouracil and intestinal metabolics
• Grantee: Claudio Fukumori
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 19/02151-2 - Development of MRI and PET/PECT dual mode theranostic nanoagent
• Grantee: Rodrigo Ken Kawassaki
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 19/21910-1 - Multi-User Equipment approved in grant 208/13877-1: equipment for high performance liquid chromatography (HPLC)
• Grantee: Luciana Biagini Lopes
• Support Opportunities: Multi-user Equipment Program
• FAPESP's process: 14/50928-2 - INCT 2014: Pharmaceutical Nanotechnology: a transdisciplinary approach
• Grantee: Maria Vitória Lopes Badra Bentley
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 18/13877-1 - Nanocarriers for localized treatment and chemoprevention of breast tumors
• Grantee: Luciana Biagini Lopes
• Support Opportunities: Research Grants - Young Investigators Grants - Phase 2